Increased Cardiovascular Risk With Lorlatinib in Patients With ALK-Mutated Lung Cancer: A Real-World Comparative Study.

BACKGROUND: The discovery of driver mutations has transformed advanced non-small cell lung cancer treatment, with ALK (anaplastic lymphoma kinase)-rearranged patients achieving longest overall survival. However, the risk of cancer therapy-related cardiovascular diseases (CTRCVDs) is underrecognized, particularly comparing second-generation ALK-tyrosine kinase inhibitors alectinib and brigatinib to the third-generation tyrosine kinase inhibitor lorlatinib, which offers the longest progression-free survival. We aimed to compare CTRCVDs risks among patients with lung cancer receiving ALK-tyrosine kinase inhibitor, assess incidence trends, and identify clinical risk factors associated with ALK-tyrosine kinase inhibitor-related CTRCVDs.

METHODS: This retrospective cohort study of 946 848 adults with lung cancer (2010-2024) using TriNetX compared CTRCVDs risk in ALK-mutated patients treated with lorlatinib versus brigatinib/alectinib. After excluding ROS1-mutated cases and 1:1 propensity score matching, 744 patients per group were analyzed. CTRCVDs, defined as myocardial infarction, stroke, arterial embolism, or heart failure, were evaluated with Kaplan-Meier analysis and Cox proportional hazards models over 2 years.

RESULTS: Lorlatinib treatment was associated with a significantly increased risk of CTRCVDs (hazard ratio [HR], 3.00 [95% CI, 1.65-5.45]; P<0.001). Incidence rose from 2.2% at 6 months to 6.6% at 3 years, versus 1.7% and 2.2% in the brigatinib/alectinib cohort. Multivariable analysis identified advanced age (HR, 1.02 [95% CI, 1.00-1.04]; P=0.04), atrial fibrillation/flutter history (HR, 2.39 [95% CI, 1.13-5.07]; P=0.002), and lorlatinib use (HR, 2.42 [95% CI, 1.57-3.72]; P<0.001) as independent predictors.

CONCLUSION: These findings underscore the importance of routine cardiovascular monitoring, particularly in older patients and those with atrial arrhythmias.